It is well established that abnormalities of the hypothalamic- pituitary-adrenal cortical (HPA) axis and sleep EEG parameters occur frequently in patients with major depression, endogenous and/or melancholic subtype. However, the reasons for and the mechanisms underlying these abnormalities remain obscure. The experiments outlined in this ADAMHA RSDA Level II application are designed to address fundamental issues related to the abnormalities of these physiologic systems. First, I plan to show that plasma ACTH and cortisol hypersecretion are synonymous with DST nonsuppression and not manifestations of two different abnormalities of the HPA axis. Second, I plan to show that DST nonsuppression is a pituitary-associated phenomena in that cortisol elevations are a consequence of increased ACTH secretion. To do so, I plan to concurrently measure both biologically and immunologically active plasma ACTH concentrations in plasma samples obtained at frequent intervals during the night under basal conditions and also after DEX administration. Third, I plan to test the hypothesis that ACTH hypersecretion/DST nonsuppression and reduced REM latency are closely linked within subjects, possibly on the basis of a common CNS abnormality underlying the dysregulation of both physiologic systems. The CNS neurotransmitter systems which might regulate both the HPA axis and REM sleep parameters will be studied with pharmacologic challenges. Normal volunteers and then patients will be given cholinegic (Ach) and serotinergic (5- HT) antagonists prior to or during sleep, and the expected reduction in nocturnal ACTH and cortisol secretion will be correlated with the degree of REM latency increase. Similarly, by the repeated administration of Ach and 5-TH antagonists, I will attempt to reproduce the REM latency and HPA axis abnormalities in normal volunteers. These challenge experiments will help to identify particular CNS neurotransmitter systems involved in the REM sleep and HPA abnormalities and to eventually establish neurotransmitter hierarchies (linkages) which underlie the regulation of these two physiologic systems in normals and depressed patients. As a complement to the human studies, studies in animals also will be performed to determine the neurotransmitter linkages associated with the regulation of the HPA axis. As a whole, both the human and animal studies will help to elucidate the neurochemical substrates and the physiologic significance of HPA axis and REM sleep abnormalities observed in patients with depression.